We all focused on one topic throughout 2020: Covid-19. No single day passed without news on the pandemic as we counted numbers of positive cases and the death toll while anticipating for a vaccine. In the meantime, we got more familiar with some of the medical processes, like phases, clinical trials, mutations, etc. for all this had to deal with the most precious gift we are given: life.

In our last issue, we touched upon the history of pharmacology and how modern-day drugs are made in an article titled “Pharmacology: The Journey of a Chemical Compound into a Drug.” Now, we will explore the multiple, lengthy phases of clinical trials that drugs must undergo and why they are imperative in order for new medicines to get approved for the marketplace.

Clinical trials are a way to test new methods of diagnosing, treating, or preventing health conditions. The goal is to determine whether a substance is both safe and effective. A clinical trial is only done when there is strong reason to believe that a new test or treatment may improve the care of patients.

A variety of treatment methods such as medications, medication combinations, new uses for existing medications, and medical devices are evaluated through clinical trials. In the United States, all new treatments must go through these trials before being approved for public sale by the Food and Drug Administration (FDA).

At the discovery and development stages, thousands of compounds may be potential candidates for development into a “drug”. After early testing, however, only a small number of compounds look promising and call for further study. The entire process of developing a drug from its pre-clinical research stage to its final marketing phase can take approximately 12 to 18 years and often costs well over $1 billion [3, 4].

Clinical trials show us what works and what does not in the realm of healthcare and are designed to answer some important questions such as:

• Does the new treatment work in people? If it does, how effective is it?
• Is it better than currently used treatments?
• If it is not better, is it just as good and cause fewer side effects?
• Does it work in some people who do not benefit from current treatments?
• Is the new treatment relatively safe? There is virtually no treatment or procedure that is without risk, but do the benefits of the new treatment outweigh the risks?

Answering these questions, while giving as few people as possible an unknown treatment, often requires several clinical trials in different phases. Each phase is designed to answer certain questions while keeping trial participants as safe as possible.

Preclinical phase

Before clinical trials can begin in humans, tests and treatments are assessed in pre-clinical research, which can involve extensive laboratory research over several years of testing on animals and human cells. This research may aim to learn the chemical compound of a drug [1]. If the initial laboratory research is successful, researchers send the data to health authorities for approval in order to begin research and testing on humans.

Once pre-clinical research results are approved, human testing of experimental drugs can begin and is typically conducted in four phases that are denoted by Roman numerals (Phase I, II, III and IV). Each phase is considered a separate trial and, after completion of a phase over many years, researchers are required to submit their data to, and then wait for approval from their local health agency (the FDA in the US) before continuing onto the next phase. If the drug successfully passes through Phases I, II, and III then it will usually be approved by the national regulatory authority for use in the general population. Phase IV trials are “post-marketing” or “surveillance” studies that are conducted to monitor how safe the product is over several years [2].

Phase I

This is the first clinical phase that involves humans. Phase I trials most often include healthy volunteers, however there are some circumstances when clinical patients are used, such as patients who have terminal cancer or HIV. These treatments possess a much higher risk for healthy individuals and could cause to become ill and contract serious adverse side effects.

In a Phase I clinical trial, doctors collect information on:

• The dose or treatment
• When it should be taken, and how often
• Any side effects or complications
• How the treatment affects patients and their preexisting conditions

One of the primary goals of Phase I studies is to find the highest dose of a new treatment that can be given safely without causing severe side effects. Although the treatment has been tested in laboratory and most likely been used in animal studies, the side effects in people cannot be known for sure. During Phase I of a clinical trial, researchers spend several months to evaluate safety, side effects, optimal dosage amounts, and formulation method for the drug on about 20 to 80 people who have no underlying health conditions.

In addition to evaluating safety and ideal dosage, specialists also look at the best way to administer the drug such as orally, intravenously, or topically. These trials are often conducted in a clinical trial clinic where the subject can be observed by full-time staff. Safety always remains the foremost concern in Phase I. The research team keeps a close eye on the people and watches for any severe side effects.

Researchers start by giving very low doses of the drug to a few patients while higher doses are given to other patients until side effects become too severe or desired effects are seen. The drug may help patients, but Phase I trials are to test a drug’s safety. If a drug is found to be safe enough, it can be tested in a Phase II clinical trial. According to the FDA, approximately 70 percent of medications move on to Phase II.

Phase 2

Phase II of a clinical trial usually involves anywhere from 50 to several hundred who are living with the condition that the new medication is meant to treat. They are usually given the same dose that was found to be safe in the previous phase. Investigators monitor participants for several months, or years, to see how effective the medication is and to gather more information about any side effects it might cause.

Most phase II studies are randomized trials where one group of patients receives the experimental drug, while a second “control” group receives a standard treatment or placebo. These studies are mostly “blinded” which means that neither the patients nor the researchers know who has received the experimental drug in order to avoid from bias. Doctors use a computer program to randomly sort volunteers into these two separate groups. Each volunteer has an equal chance of ending up in any of the groups and are randomly put in any group.

This allows investigators to provide the pharmaceutical company and the health authority with comparative information about the relative safety and effectiveness of the new drug. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered to not to work as planned or to have toxic effects. The FDA estimates that roughly one-third of experimental drugs successfully complete both Phase I and Phase II studies.

Phase II clinical programs historically have experienced the lowest success rate of the four development phases. In 2010, the percentage of Phase II trials that proceeded to Phase III was 18% [5] and only 31% of developmental candidates advanced from Phase II to Phase III in a large study of clinical trials conducted during the period of 2006 – 2015 [6].

Phase III

Phase III of a clinical trial usually involves up to 3,000 participants who have the condition that the new medication is meant to treat. These participants must include men, women, and people of different ages and ethnic groups in many places across the country (or even around the world) at the same time. This helps doctors learn how treatment works in different people with different genetic backgrounds, races, and ethnicity. These studies tend to last longer – up to several years – than Phase I and II studies.

One of the additional purposes of Phase III is to evaluate how the new medication works in comparison to existing medications for the same condition. To move forward with the trial, investigators need to demonstrate that the medication is at least as safe and effective as existing treatment options. Due to the larger number of participants and longer duration of Phase III, rare and long-term side effects are more likely to show up during this phase.

There can be more than two treatment groups in Phase III trials. The control group may receive the current standard-of-care treatment for their illness while other groups receive the new treatment on trial. Phase III trials are usually double blinded to eliminate bias when interpreting results.

Placebos may be used in some Phase III studies, but they are never used alone if there is a treatment available that works. Sometimes, a patient who is randomly assigned to the placebo for part of the study will at some point be offered the standard treatment as well. As with other trials, patients in Phase III clinical trials are watched closely for side effects, and treatment is stopped if they become too hard to manage.

Every patient in a Phase III study is watched closely, and the study will be stopped early if the side effects of the new drug are too severe or if one group has significantly better results. Phase III clinical trials are often needed before the FDA will approve the use of a new drug for the general public. If researchers demonstrate that the medication is at least as safe and effective as others already on the market, then the FDA will usually approve the medication.

In the United States, when Phase III clinical trials (or sometimes Phase II trials) show a new drug is more effective or safer than the current treatment, a new drug application (NDA) is submitted to the FDA for approval. The FDA reviews the results from the clinical trials and other relevant information.

Based upon the review, the FDA then decides whether to approve the treatment for use in patients with the illness the drug was tested on. If approved, the new treatment often becomes a standard of care and newer drugs may be tested against it before they can be approved. If the FDA feels that more evidence is needed to show that the new treatment’s benefits outweigh its risks, it may ask for more information or even require that more studies be done. Once Phase III is complete, a pharmaceutical company can request FDA approval to begin marketing the drug. Roughly 25 to 30 percent of medications move on to Phase IV.

Phase IV

Phase IV trials test new drugs that are approved by health authorities and often are called Post Marketing Surveillance Trials. The drugs are available for doctors to prescribe to patients, but Phase IV studies might still be needed to answer important questions. In previous clinical phases the drug may not have been tested for interactions with other drugs, or on certain population groups, such as pregnant women, who are unlikely to subject themselves to trials. This phase involves thousands of participants and can last for many years. Investigators use this phase to get more information about the medication’s long-term safety, effectiveness, and any other benefits.

This is often the safest type of clinical trial because the treatment has already been studied a lot and has likely been given to many people. Phase IV studies look at safety over time. These studies may also look at other aspects of the treatment, such as quality of life or cost effectiveness.

Phase IV studies can result in a drug or device being taken off the market or restricted depending on the findings in the study. Unless an adverse effect of the approved drug is shown or the drug is accepted as safe, it will stay on the market and also in Phase IV forever.

This clinical trial algorithm has come out after many scientific studies. Every point of the clinical trials, and possible problems, have been clarified by policies which may differ from country to country. At the end, clinical trials are a very safe and cautious method of finding out the safest and most effective treatment, or diagnostic method, for people. During clinical trials, scientists are very careful about ethical issues and try not to harm any living organisms, be them animals or humans. There is an ongoing public debate over pharmaceutical companies. While some think they play a major role in the emergence of many methods and scientific developments to benefit human health, others doubt their motivations and questions their contribution to the public good. This debate will surely continue for a long time, but under the current circumstances, pharmaceutical companies are found in the center of all these clinical trials described in this article. Regardless of the truth behind these doubts, it is important to be always aware of the priceless value of life, that it has been given to us and all living things as an inalienable right and a precious gift, and that it is a major responsibility take care of it well and seek healing when needed.

• https://www.nccn.org/patients/resources/clinical_trials/phases.aspx
• “The drug development process”. US Food and Drug Administration. 4 January 2018. Retrieved 17 August 2020
• Holland J (2013). “Fixing a broken drug development process”. Journal of Commercial Biotechnology. 19. doi:10.5912/jcb588.
• Adams CP, Brantner VV (2006). “Estimating the cost of new drug development: is it really 802 million dollars?”. Health Affairs. 25 (2): 420–8. doi:10.1377/hlthaff.25.2.420. PMID 16522582.
• “New drugs failing Phase II and III clinical trials”. MedCity News. 2011-06-02.
• “Clinical Development Success Rates 2006-2015” (PDF). bio.org. Retrieved 2018-02-11.

It was too early for Melanie to congratulate herself because the aliens would always be after her. They would always be looking over her shoulder, keeping track of what she did, trying to read her mind…

Melanie rolled around in bed and looked at her digital clock. It read: 7:39

She groaned to herself. That must mean it was time…

She got out of bed and looked around her room. Everything seemed normal. The sun appeared to be bright as it flooded through her window with the red curtains. Her clinical psychology text books on her desk were exactly where she remembered putting them. Her bed was in the correct position along the wall.

She deliberately avoided looking at the mirror.

She was safe for now; the aliens hadn’t come for her yet. But she knew her neighbor was a Russian spy so it was only a matter of time before he told the aliens about the key she had found…

…the key she had safely hidden under her bed in a Cheerios cereal box. No one could find it there.

Melanie carefully examined the floor she would walk on. She was certain it was safe to walk, but those aliens really knew how to set booby traps. She really had to be prudent-or else!

She carefully placed her foot on the carpet. The carpet had a collage of various, colored squares on it. Aliens always had a hard time getting into her room, but they had implanted sensors under the floor that sent them a signal every time she stepped on the red squares. They did this so they could tell how often Melanie was in her room.

But Melanie had figured out a way how to fight them. If she just avoided those red squares, they would never know.

Stepping on her toes, she tiptoed around the red squares and reached the other side of the room. She carefully checked the books on the desk, the position of her bed, the window and the curtains-avoided the mirror-and then came out of the room.

She quietly pulled her door shut and peeked over her shoulder down the hall.

Oh no! There were too many mirrors!

The mirrors stretched along the wall on either side, disrupted only by the occasional bedroom door. But there were only supposed to be one of them between the master bedroom door and the bathroom.

Hmmm; could this be the aliens?

In any case, she had to avoid the mirrors – the aliens must NOT find out about the key!

She got onto her hands and knees. If she could just slide under the line of the mirrors, she would be safe. Thus she scrambled to the other side, carefully avoiding the red squares on the carpet, and finally got up on her feet at the end of the hall.

It was too early for Melanie to congratulate herself because the aliens would always be after her. They would always be looking over her shoulder, keeping track of what she did, trying to read her mind… Oh no, she hadn’t thought about that! How should she protect her mind?

She would stick it out as long as she could. There was no way she would allow those aliens to get the key! Not while she was still alive.

She had to eat though, or else how could she have the strength to protect the key?

Melanie opened the cereal cupboard and confronted a bunch of boxes. There were Cheerios, Honeycombs, Pops, Fruit Loops, Apple Jacks and many more.

Pleased with the variety, she reached for the Cheerios.

Oh no!

She remembered something.

Last night, she had seen only Honeycombs in the cupboard. Yes, she’d Melanie had gone out with her mother, and they’d only bought Honeycombs. Where did all the others come from?

How could she not have understood? It was the aliens. They must know she had hidden the key in a cereal box. But they didn’t know which one, did they? So they put a bunch of cereal boxes here to see which one she would pick.

But Melanie would not lose!

“Oooooo!” she cooed loudly. “We have Honeycombs! Yum! I love Honeycombs!”

And that’s what she got out of the cupboard and put on the kitchen island. She had to distract the aliens.

She got out her bowl-not the red one; you could never be too careful-and a spoon. These she laid down beside the cereal box. When she had retrieved the milk from the fridge however, things had changed.

There were five sets of bowls and spoons on the island!

She calmed herself down.

This had happened before. It was the aliens’ way of saying they knew she was lying to them.

But she could always get around it.

She touched the first bowl and her finger slipped right through it. Nope, not this one.

Her fingers slipped through the second one but jammed into the third. Hah! That one was the right one.

She poured her cereal and milk into it. Suspiciously, the remaining two bowls somehow filled themselves.

But everything was alright. It didn’t matter how hard those aliens would try to intimidate her, she would be strong.

However, she was very sad. She didn’t realize at the time, but before she found the key – before the aliens and the Russian neighbor – everything had been so easy, so safe.

It was hard to appreciate a good thing when its loss was unimaginable. She had never believed in aliens and now they were in her life, changing things, manipulating her. They were always there.

Her breakfast finished, she finally pulled herself together. It would be alright. Everything would be alright. She was sure of it now.

As she re-entered the hallway, she saw that the mirrors were gone. There was only one, exactly between the master bedroom and the bathroom.

Before entering the bathroom, Melanie paused and looked at herself in the mirror. There was a snake coiled around her temple.

She instinctively reached up but couldn’t feel it.

“You’re not real,” She said to it. “No, none of it is real… the key? The aliens?”

The snake in the mirror bobbed its head in a nod.

It was a wonder why anyone would believe only what they could see when Melanie had to doubt everything in her life.

Something caught her attention and the recognition of her illness faded instantly from her mind. There was red smoke coming from her bedroom.

Oh no, the aliens must know! They must have understood about the Cheerios cereal box!

The Plaza of Abraham is a place that will host and welcome people of all faiths, especially followers of the Abrahamic faiths. The Plaza is envisioned as being built on approximately ten acres of land. On this land a large circle, called Abraham’s Circle, has been planned. Three places of worship are positioned on the circle. If the circle were a clock, at 3 o’clock there is a mosque, at 7 o’clock a synagogue, and at 11 o’clock a church is located. These will be active places of worship. People will feel safe and comfortable in these places. To illustrate this feeling of safety and comfort for our readers, we would like to them to imagine that they are going to stay in a foreign city, where they do not know the language. They may well prefer to stay in a hotel which is part of a well-known chain. A significant number of people visiting foreign cities would prefer to stay in a well-known hotel, because even though they have come to this foreign city to explore and discover new, fascinating facts of history and geography, even though they are there to visit places, meet people and otherwise live an experience that is novel and different from what their experience at home, they would still prefer to stay in a place that is familiar to them, as a starting point. In the same way do the places of worship on the Circle of Abraham serve as safe and comfortable starting points for people who want to discover other religions. They give the message: Come, you are safe here.

The imams, the rabbis and the priests to be employed in these places of worship are not simply religious leaders; they are scholars as well. They can and are willing to study different religions without any prejudice. They are also guides for other people in the dialogue experience, they serve to protect this effort from falling into a common dilemma: the blind leading the blind. In interfaith dialogue, in efforts where knowledgeable people are not involved, ignorant members of the groups can easily turn the atmosphere into a critical one. In order to prevent such occurrences, these scholarly religious leaders have authority over the people of their faith and there is an internalized approach to dialogue, based on such principles of interfaith dialogue as courtesy, respect, self-critical examination, abandonment of preconceptions and seeking first to understand before trying to be understood.

The plaza will also have a computerized digital library that provides access to digital copies of the main sources for all three religions. Scholars of the different religions will come together to discuss recent issues, and past and possible future interpretations of the religious sources. These efforts focus on searching for interpretations of the sources that foster peace, harmony and mutual coexistence instead of animosity.

A common value to each of these three faiths is hospitality. To bring this common value to the fore, Abraham’s plaza has a feast table covered by a large tent. Once a year a celebration will be held that will last for many days and weeks. Through this event, the People of the Book (as described in the Qur’an) become the People of the Tent. A feast like this is also likely to attract young people. The feast itself and the possibility of making friends from other faiths and nations is likely to be attractive to them.

We envision replicas of Abraham’s Plaza being constructed on all continents of the earth: Europe, Asia, the Americas, Australia and Africa. We envision plazas in major cities, as well as in any small towns where there is a representation of all these faiths. We live in a strange age. We have the best, most widespread and fastest means of communication and transportation to date. Yet the world still faces challenges of misunderstanding and animosity. Projects like the Abraham’s Plaza are needed to get everyday people involved in an interfaith dialogue and in the active pursuit of a more peaceful world.

Reference

• Feiler, Bruce. Abraham, a Journey into the Hearts of Three Faiths. Harper Collins Publishers, 2002.

always regard

whatever pleases and

displeases yourself as the measure.

Wish that others

may receive those things

that are most pleasing to you,

and do not forget that

whatever conduct displeases you

will displease others.

If you do this,

you will be safe

not only from misconduct

and bad behavior,

but also from hurting others.

‘They have run away again. We warned them not to do it, but our words don’t have much influence on them. This is the third time.

‘Why do they run away?’ asked a teacher

‘I don’t know. Perhaps because they want to be vagrants, wanderers.’

‘How did you manage to find them the last time?’

‘The first time we caught up with them in the bus-station. The last time they were seen sleeping on park benches. There was martial law at the time and soldiers patrolling the curfew spotted them and kept an eye on them – then, we were informed and fetched them. We told them very clearly that such behaviour would get them into serious trouble but, as I say, our warnings have proved useless.’

The three like-minded friends had made up their minds to escape this time by train. After they had bought their tickets, they tried to get onto the platform. An experienced ticket-collector was able to recognize that they were fugitives. However, he said to them:

‘It is not safe here, there are a lot of thieves about. Give me your tickets and money, and I shall keep them safe for you until the train comes. Believe me, I think of you as my own children.’

The young boys believed the ticket-collector and gave him their money and tickets. The ticket-collector informed security and asked them to find out who the students were and then to inform their school authorities.

A station security officer came up to the students and chatted to them in a kind, friendly way. When he found out what he wanted to know, he informed the school authorities.

The house-master came to the station before the train was due to leave. He collected the students and returned them to their dormitory. This time they would get a beating, he thought, because every kind of warning had been given to them. On the way to the dormitory, they met the Headmaster. When the situation to him was explained to him, he said to the house-master:

Bring me three iron bars. I am going to give a lecture and these students should attend it.

As the house-master went to get the iron bars, he thought: ‘Good Lord! Isn’t one bar enough? Is it likely to break?! Anyway, there must be some reason for it, though I can’t imagine what it is.’

He brought the three iron bars to the Headmaster .The Head then lectured the students, who listened to him in a bored, anxious way like patients waiting for an operation. Then, he said:

‘OK. Now, come, follow me.’ He led them all into the next room. Surprisingly, he spoke first to the house-master:

Take off your shirt, as I am taking off mine. And you boys, pick! It is we who deserve the beating. If we had set a good example, if we had been able to recognize and encourage the humanity in your souls, you would never have wished to be runaways. We stand before you, naked to the waist. Strike us as you wish!’

The boys who were already worn out when they entered this room, now flung themselves to the floor in misery:

‘Do whatever you want to us, but please forgive us,’ they said tearfully.

The Headmaster had not been joking. He had meant what he said. He had reached his conclusion only after serious self-examination. When he recognized in the boys’ manner and tone a desire to return voluntarily, he changed his mind about punishment. None of the boys ever ran away again.